Dopamine, a neurotransmitter in the central nervous system, has been implicated in numerous neurological disorders. For example, it has been hypothesized that excess stimulation of dopamine receptor subtypes may be linked to schizophrenia. Additionally, it is generally recognized that either excessive or insufficient functional dopaminergic activity in the central and/or peripheral nervous system may cause hypertension, narcolepsy, and other behavioral, neurological, physiological, and movement disorders including Parkinson's disease, a chronic, progressive disease characterized by an inability to control the voluntary motor system.
Dopamine receptors have traditionally been classified into two families (the D1 and D2 dopamine receptor families) based on pharmacological and functional evidence. D1 receptors preferentially recognize the phenyltetrahydrobenzazepines and generally lead to stimulation of the enzyme adenylate cyclase, whereas D2 receptors recognize the butyrophenones and benzamides and often are coupled negatively (or not at all) to adenylate cyclase. It is now known that at least five genes exist that code for subtypes of dopamine receptors: the D1, D2, D3, D4 and D5 receptor subtypes. The traditional classification, however, remains useful, with the D1-like class comprising the D1 (D1A) and the D5 (D1B) receptor subtypes, whereas the D2-like class consists of the D2, D3 and D4 receptor subtypes. Variation can occur also through splice variants (e.g., the D2L and D2S splice variants), as well as through different alleles (e.g., multiple repeats of the D4 gene).
Central nervous system drugs exhibiting affinity for the dopamine receptors are generally classified not only by their receptor selectivity, but further by their agonist (receptor activating) or antagonist (receptor blocking) activity. While the physiological activities associated with the interaction of dopamine with the various receptor subtypes are not fully understood, it is known that ligands exhibiting selectivity for a particular receptor subtype will produce more or less predicable neuropharmacological results. The availability of selective dopamine receptor antagonist and agonist compounds permits the design of experiments to enhance understanding of the many functional roles of D1 receptors and can lead to new treatments for various central and peripheral nervous system disorders. In addition, if agonists were available with high affinity for both the D1 and D2 receptors, these agonists could be used under circumstances where binding to both D1 and D2 receptors is beneficial.
The early focus of dopamine receptor studies was on the D2 family, but a critical role of the dopamine D1 receptor in nervous system function has become apparent recently. That early work on selective D1 receptor ligands primarily focused on molecules from a single chemical class, the phenyltetrahydrobenzazepines, such as the antagonist SCH23390 (1): Several of the phenyltetrahydrobenzazepines were found to be D1 receptor agonists; however, the agonists derived from this class [including, for example, SKF38393 (+)-2] generally were partial agonists. Even SKF82958, purported to be a full agonist, recently has been shown not to have full intrinsic efficacy in preparations with decreased receptor reserve. The differentiation between D1 agonists of full and partial efficacy is important to the medical research community because this may influence the actions of these compounds on complex central nervous system mediated events. For example, two full agonists (dihydrexidine and A-77636) have exceptional antiparkinsonian effects in the MPTP-treated monkey model, whereas partial agonists are without significant activity. More recent data suggest that full and partial agonists also differ in their effects on other complex neural functions. In addition, there are receptor-mediated events (e.g., recruitment of G proteins and associated receptor kinases) that can affect agonist activity. These latter biochemical events may occur independently of the changes in second messenger levels (e.g., cAMP) mediated by a drug.
Accordingly, researchers have directed their efforts to design ligands that are full agonists (i.e., have full intrinsic efficacy) for the D1 receptor. One such compound is dihydrexidine (3), a hexahydrobenzo[a]phenanthridine of the formula: The structure of dihydrexidine (3) is unique from other D1 agonists because the accessory ring system is tethered, making the molecule relatively rigid. Molecular modeling studies of dihydrexidine (3) have shown that the compound has a limited number of low energy conformations, and the aromatic rings are held in a relatively coplanar arrangement in all of these conformations. The recent elucidation of the configuration of the active enantiomer of dihydrexidine (3) was consistent with predictions from this model.
Unlike other high affinity, high intrinsic activity D1 agonists like 3-substituted aminomethylisochromans, dihydrexidine (3) provided a semi-rigid template for developing a dopamine ligand model. The essential features of this model include the presence of a transoid β-phenyldopamine moiety, an equatorially oriented electron lone pair on the basic nitrogen atom, and near coplanarity of the pendant phenyl ring with the catechol ring. The dihydrexidine-based model has a transoid β-phenyldopamine moiety, whereas the dopaminergic phenyltetrahydrobenzazepines have a cisoid β-phenyldopamine conformation. The dihydrexidine-based model has served as the basis for the design of additional D1 receptor agonists. The design and synthesis of D1 receptor agonists having high intrinsic activity is important to the medical research community due to the potential use of full agonists to treat complex central nervous system mediated events, and also conditions in which peripheral dopamine receptors are involved. For example, the compositions of the present invention have potential use as agents for lowering blood pressure, and for affecting lung and kidney function.
One embodiment of the present invention is a novel class of dopamine receptor agonists of the general formula: and pharmaceutically acceptable salts thereof, and pharmaceutical formulations of such compounds. The present compounds are useful for treating patients having a dopamine-related dysfunction of the central nervous system (as evidenced by an apparent neurological, psychological, physiological, or behavioral disorder), as well as conditions in which peripheral dopamine receptors are involved (including target tissues such as the kidney, lung, endocrine, and cardiovascular systems).